REVIEW ARTICLE

Herpes Zoster Ophthalmicus Review and Prevention

Andrew R. Davis, M.D. and John Sheppard, M.D.

In primary VZV infection (i.e., chickenpox or varicella) lesions

Abstract: Varicella-zoster virus (VZV) is the etiologic agent of both are generally noted to be in varying stages with simultaneous
chickenpox and Herpes zoster (HZ). In the United States, there are around maculopapular, vesicular, and scab components. In herpes zoster
one million cases of HZ per year. Ten percent of HZ cases are subtyped as (HZ), lesions are all typically in the same stage given the
herpes zoster ophthalmicus (HZO) specifically and involve the V1 dermatologic infection is localized and originates from the
distribution. Herpes zoster ophthalmicus is a significant cause of blindness surrounding nerves. Chickenpox is generally self-limited but can
in the United States. This article will provide a basic overview of VZV, HZ,
be devastating in immunocompromised hosts. After establishing
and HZO with a focus on preventative measures in an effort to prevent
blindness through improving clinician awareness and education. The
a primary infection, VZV remains latent in sensory dorsal root
differences in clinical effectiveness and duration of effectiveness of the ganglia and the trigeminal ganglion. Varicella-zoster virus is kept
live (Zostavax) and recombinant vaccines (Shingrix) are illustrated. There is at bay in the sensory ganglia by the cell-mediated branch of the
now a trend toward using the recombinant vaccine as recommended by the immune system. When cellular-mediated immunity is compro-
Advisory Committee for Immunization Practices (ACIP) for healthy adults mised by HIV infection, use of immunosuppressive agents, or
50 or older. certain malignancies and lymphoproliferative disorders, VZV is
Key Words: Herpes zoster—Varicella zoster virus—Herpetic uveitis—
permitted to arise from its latent state and spread through sensory
Herpetic keratitis—Vaccination. neurons by way of microtubules. Subsequently, epithelial cells
become infected and the clinical entity known as HZ result.1,3,4,6,7
(Eye & Contact Lens 2019;45: 286–291)

HERPES ZOSTER
INTRODUCTION The individual lifetime risk for HZ is estimated to be around
Varicella-zoster virus (VZV) is a part of the Herpesviridae 30%8 and is traditionally believed to be more common in older
family and therefore has similar characteristics as its family individuals due to decreased cellular-mediated immunity. Reacti-
members. Varicella-zoster virus is enveloped, has double- vation typically occurs unilaterally and along the thoracic or lum-
stranded DNA, and establishes latency.1 The envelop of the virus bar dermatomes. Patients often complain of neuralgia in the given
is derived from host cells, and thus, it is sensitive to detergents. dermatome before the onset of erythema that progresses to a mac-
Seven specific glycoproteins have been identified (gB, gC, gE, gH, ulopapular rash followed by progression to a vesicular rash. In
gI, gK, and gL) that serve as clinical markers for cell-mediated contrast to chickenpox, HZ lesions are typically in the same stage.1
immunity (CMI) and humoral immunity to VZV. Several different It is uncommon to have lesions of the rash at different stages. For
genotypes have been identified and vary geographically. The main example, vesicles with scabs would be abnormal in HZ. These
genotypes in the United States and Europe are B and C, whereas J, lesions typically form over the course of 5 days and resolve after
J2, and A1 are more common in Africa and Asia.2,3 The virus 10 to 15 days, but healing of the dermis can be prolonged for up to
spreads by direct cell-to-cell contact and is spread through the 1 month. Immunocompromised hosts can have lesions for longer
respiratory tract. Initial viral particle replication is believed to begin and are at a greater risk for dissemination.1,3 Herpes zoster oph-
in the nasopharynx as polymerase chain reaction samples of naso- thalmicus (HZO) specifically affects the V1 distribution. As the V1
pharynx secretions have been found to be positive for VZV DNA nerve innervates many ocular and periocular structures, a variety of
in exposed persons. Viremia occurs through lymphatic spread of clinical entities result. To understand these entities, one must
viral particles from the nasopharynx to circulating T lymphocytes. review the anatomy of the V1 nerve.3,7,9,10
The virus arrives at the skin, and epithelial cells become infected
with the virus leading to chickenpox (varicella).4,5
CLINICAL MANIFESTATIONS OF HERPES
From the Department of Ophthalmology, Eastern Virginia Medical School, ZOSTER OPHTHALMICUS
Norfolk, VA. After the acute onset of neuralgias, an erythematous rash
J. Sheppard (Novartis, Bausch+Lomb, Allergan), The remaining author develops. This is followed by a maculopapular rash and vesicles
has no conflicts of interest to disclose.
Address correspondence to John Sheppard, M.D., Virginia Eye Con-
that form unilaterally in any, or all, of the branches of the V1 nerve.
sultants/Cincinnati Eye Institute, 241 Corporate Boulevard, Norfolk, VA There are varying estimates of the number of patients with HZO
23502; e-mail: jsheppard@vec2020.com. who present with ocular involvement and essentially any of the
Accepted January 12, 2019. ocular or periocular structures can be involved (see above anatomy
DOI: 10.1097/ICL.0000000000000591 review)3,11 (Fig. 1 and Table 1).

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Eye & Contact Lens  Volume 45, Number 5, September 2019 HZO Review

Commonly, the periocular skin and eyelids become involved with reaction form viral invasion of endothelial cells and may present
vesicles, erythema, and edema. Patients tend to present with unilaterally with diffuse or localized folds of Descemet’s membrane, stromal
marked swelling and vesicles of the forehead, scalp, and eyelids. and epithelial edema, and typically presents after 1 week. Disci-
Secondary bacterial cellulitis can result commonly from Gram-positive form keratitis, although infrequent, manifests as multiple areas of
organisms and require systemic antibiotic treatment. Chronically, corneal edema with minimal infiltration and intact overlying epi-
cicatricial changes to the eyelids may lead to trichiasis or lagophthalmos thelium. This unique clinical finding is believed to be secondary to
that is severe enough to require surgical correction. The puncta often a viral infection in the endothelium or an immune reaction to viral
become scarred, and pigmentary changes of the dermis are frequently particles in the stroma, and this is similar to HSV.3,12,13
present long after initial infection. Infrequently, pain without an Typically, uveitis presents as either a granulomatous or non-
eruptive phase may occur, and this is known as zoster sin herpete.3,12,13 granulomatous iridocyclitis and vaso-occlusive iris atrophy occurs
Conjunctivitis presents with a papillary or follicular reaction during acute infection.3,12,13 Trabeculitis may ensue resulting in
with or without membranes and pseudomembranes. Conjunctival a secondary glaucoma.
vesicles or petechial hemorrhages are frequent. In cases of severe During the chronic phase, sequelae of infection manifest that
conjunctival involvement, symblepharon formation occurs.3,12,13 often lead to chronic blindness. Corneal nerve damage leads to
Episcleritis may be evident early on in the disease course and decreased corneal sensation and subsequent epithelial defects
can last up to several months. Scleritis may lead to thinning of known as neurotrophic keratopathy. These sterile ulcerations
the sclera and staphyloma formation.3,12,13 regularly become secondarily infected. Interstitial keratitis sel-
domly becomes persistent and refractory leading to corneal neo-
Corneal Involvement vascularization, opacification, and lipid deposition. Damage to the
Herpes zoster ophthalmicus can involve any of the corneal layers. endothelial cells may lead to chronic corneal edema. Glaucoma
There are generally three phases to corneal involvement: acute (active habitually develops as a result of trabeculocyte damage or steroid
viral infection), subacute (immunologic response to viral infection), use.3,12,13 It should be noted that acute VZV is oftentimes followed
and chronic (sequelae of viral infection). In response to active viral by recurrent and longstanding infection leading to iritis, and den-
replication, patients typically present with a punctate epithelial dritiform epithelial keratitis.
keratitis (see clinical picture) with swollen epithelial cells. Pseudoden-
drites may form acutely and represent a conglomeration of punctate Posterior Segment Manifestations
epithelial keratitis, they may also be seen chronically. Pseudodendrites Making our way to the posterior segment, HZO has been shown
are usually raised, edematous epithelial lesions that occur within a few to cause optic neuritis, and there are several case reports of optic
days after HZO onset. They have blunt ends, and there is no loss of neuritis after varicella vaccination in immunocompromised pa-
cornea epithelium as in HSV. Pseudodendrites only minimally stain tients.14,15 In addition, VZV every so often involves the retina. In
with fluorescein or rose Bengal.3,12,13 (Figs 2 and 3). fact, the herpes viruses are the leading cause of acute retinal necro-
Because of an immunologic response of the viral infection, sis (ARN). This syndrome is characterized by a retinitis of yellow-
anterior stromal infiltrates (also known as nummular keratitis) white deep appearing lesions that start in the peripheral fundus and
immediately under Bowman’s layer can occur and typically present become contiguous around the periphery as they progress toward
after 10 days. Anterior infiltrates occur deep to previous epithelial the posterior pole. Vasculitis, vitritis, and optic neuropathies are
lesions.13 Endotheliitis is also believed to occur due to an immune common components of ARN. The macula is usually not involved.

FIG. 1. Sensory distributions of the trigeminal

nerve.

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A. R. Davis and J. Sheppard Eye & Contact Lens  Volume 45, Number 5, September 2019

TABLE 1. Neuroanatomy of the Trigeminal Nerve

Division of
Trigeminal Nerve Branch Sub-branch Area of Innervation Important Points

Ophthalmic (V1) Top of head, forehead, upper eyelid, and nose. Sensory only except for postganglionic fibers
received from the internal carotid11,12
Frontal n. (See sub-branches) Most frequently involved branch in HZO.11,13
Outside of the muscle cone.
Supratrochlear n. Skin of the upper eyelid, forehead, and middle
and supraorbital scalp.11,13
n.
Lacrimal n Supplies the lacrimal gland, lateral upper eyelid skin,
and lateral conjunctiva of the upper eyelid (lateral
palpebral conjunctiva).13
Nasociliary Serves as the pathway for VZV to reach the eye
itself.11,13 Inside the muscle cone.
Short ciliary nn. From the ciliary ganglion, short ciliary nerves11,13 arise. A branch of the nasociliary nerve11,13 provides
postganglionic sympathetic nerve fibers to
the ciliary ganglion. Please note, these
postganglionic fibers do not synapse in the
ciliary ganglion.
Long ciliary nn. Sensory of the globe and cornea, the sympathetic
fibers that were received from the internal carotid
artery innervate the dilator muscle11,13
Posterior and Supply the ethmoidal air cells, sphenoidal sinus, The external nasal nerve (noted as the nasal
anterior anterior cranial fossa, nasal cavity, and skin of the nerve in the picture above), a branch of the
ethmoidal nerves lower aspect of the nose11,13 anterior ethmoidal nerve supplies the tip of
the nose and thus is involved when there is
a positive Hutchinson’s sign11,13
Infratrochlear Runs medially and supplies the lacrimal sac, medial
nerve aspect of the upper and lower eyelid skin, medial
conjunctiva, and caruncle as well as the upper
aspect of the skin overlying the nose11,13
Maxillary (V2) Over the maxilla, lower eyelid. Sensory only11,12
Infraorbital Of note, the infraorbital nerve of V2 supplies the lower There should be limited vesicular involvement
nerve eyelid skin and lateral nose.13 of the lower eyelid if the VZV infection only
involves V1 given the anatomical
separation13
Mandibular (V3) Jaw, lateral head. Motor and sensory11,12

Source of table: self-created.

HZO, herpes zoster ophthalmicus; VZV, varicella-zoster virus.

As the peripheral lesions resolve, retinal breaks may occur and rheg- consists of a live, attenuated virus from the Oka strain of VZV
matogenous retinal detachments ensue. Variants of ARN with only isolated in Japan. Currently, the Center for Disease Control (CDC)
patches of peripheral retinal whitening have been reported.16 Progres- recommends two doses of the chickenpox vaccine for healthy chil-
sive outer retinal necrosis (PORN) occurs because of VZV and is more dren. In addition, adults without evidence of immune compromise,
common in immunocompromised patients. Comparable with ARN, women who are healthy at prenatal/postnatal time points, and HIV-
the retinitis in PORN starts with areas of retinal whitening that merge. infected children and adults with adequate T-cell immunity if they
However, the posterior pole usually becomes involved earlier. There is do not have evidence of immunity to VZV18 based on lack of
usually is not vitritis in PORN, and the vessels are only minimally antibodies are recommended to be vaccinated. Although the
involved in PORN as compared with ARN.3,5,14 vaccine has shown marked efficacy in reducing chickenpox, the
The CNS becomes involved in certain instances leading to Oka-attenuated virus still establishes latency and has the potential
a meningoencephalitis, encephalitis, and strokes.1 Ocular motor to cause HZ. However, the incidence of HZ secondary to the
palsies can affect the third, fourth, or sixth nerves resultant from varicella vaccine (Oka strain of VZV) is substantially lower in
a vasculitis that occurs in the orbital apex.15 Postherpetic neuralgia children receiving chemotherapy for leukemia compared with chil-
is a significant sequelae of HZO or HZ that preferentially affects dren receiving chemotherapy who had wild-type VZV infections.
the elderly and immunocompromised. Patients often experience In addition, there is concern that widespread varicella vaccination
recurrent pain in the affected area significant enough to reduce will lead to a reduction in wild-type virus exposure, and as a result,
their overall quality of life and is described as a shooting, sharp this reduction in wild-type virus exposure could potentially
pain. Postherpetic neuralgia frequently lasts for months and inter- decrease an individual’s immunity to latent wild-type infections
feres with activities of daily living.17 and theoretically cause a higher incidence of wild-type VZV reac-
tivation and subsequent HZ.18,19

VACCINATION Herpes Zoster Vaccination: Live Vaccine

Varicella Vaccination (Zostavax, ZVL)
After the introduction of the varicella vaccine in the United Most of the adults in the United States currently have been
States in 1995, the incidence of varicella reduced somewhere exposed to VZV,1 and this does not need to be confirmed serolog-
between 76 and 87% between 1995 and 2000.16 The vaccine itself ically. As patients age, they will be more likely to have

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Eye & Contact Lens  Volume 45, Number 5, September 2019 HZO Review

millimeter or less than 15% total lymphocytes, those who are on

immunosuppressant therapy including high-dose steroids, those
with hematologic or lymphatic malignancies, those who have evi-
dence of impaired cellular immunity, those undergoing hematopoi-
etic stem cell transplantation, and those receiving a recombinant
human immune mediator or immunomodulator (especially anti-
TNF factors such as adalimumab, infliximab, and etanercept)
should not receive the vaccine.23
The shingles prevention study (SPS) was a multicenter random-
ized control study that enrolled 38,546 adults 60 years or older to
receive the Oka/Merck VZV vaccine (zoster vaccine) or a placebo.
The main outcome measures were incidence and severity of HZ
and PHN, and the burden of illness caused by HZ. The patients
were followed for a median of 3.12 years, and the vaccine was
shown to reduce the burden of illness of HZ by 61.1%, the
FIG. 2. Punctate epithelial keratitis. incidence of HZ by 51.1% (P,0.001), and the incidence of PHN
by 66.5% (P,0.001).20
compromised CMI and reactivation of HZ. As such, HZ vaccina- The short-term persistence substudy followed 7,320 of the
tion is indicated to prevent HZ and its complications. vaccinated patients and 6,950 of placebo patients from the SPS
The live HZ vaccine (Zostavax, ZVL) is a lyophilized formu- through 4 years after vaccination. The burden of illness was
lation of a live, attenuated VZV strain and is the same strain used in reduced 50.1%, the incidence of PHN was reduced 61%, and the
varicella vaccines although at a much higher dose (14·) to stimu- incidence of HZ was reduced 39.9%.22
late cellular immunity. The vaccine is given as a 0.65-mL sub- The long-term persistence study enrolled 6,867 SPS vaccine
cutaneous injection in the deltoid region and is a one-time recipient patients and followed them yearly from year 7 after
vaccination.20 vaccination to year 11 after vaccination. The burden of illness
The Advisory Committee for Immunization Practices (ACIP) was reduced 37.3%, the incidence of PHN was reduced 35.4%,
previously recommended the ZVL as the gold standard for people and the incidence of HZ was reduced a meager 21.1%. The
60 or older whether they reported a previous history of varicella vaccine efficacies in the STPS and LTPS studies waned with
unless a contraindication existed. Now, the ACIP recommends the time, and the overall efficacy of the vaccination came into
live vaccine for patients older than 60 only if a patient is allergic to question. 6 If a patient is vaccinated at 60 years of age (as the
the recombinant vaccine (Shingrix, RZV).21 In 2011, the FDA ACIP recommended previously), by the age of 71 when pa-
approved the ZVL for individuals 50 to 59 years of age. An exten- tients are generally believed to be more susceptible, the vac-
sive review in 2013 by the ACIP was undertaken regarding cine has likely lost most of its effect (given the results of the
whether the vaccination should be recommended for this age LTPS). This leaves older patients vulnerable to HZ. As boos-
group, but they concluded not to expand the indication given there ters were not ever recommended, the overall effectiveness of
were limited data on long-term protection provided by the HZ the zoster vaccine in our aging baby-boomer population was
vaccine22 debatable. There is therefore a need for a vaccine with a pro-
Generally, there are three groups of people in which ZVL is longed efficacy.
contraindicated: pregnant women, patients with an anaphylactic
allergy to any of the vaccine’s components, and those who are Herpes Zoster Vaccination–Recombinant Vaccine
immunocompromised. AIDS patients with a CD4 ,200 per cubic (Shingrix, RZV)
Recent work has been underway to create a recombinant
varicella vaccine containing VZV glycoprotein E using the
ASO1B adjuvant system. The recombinant vaccine is given as
two intramuscular injections 2 to 6 months apart, and both in-
jections are required for efficacy.24 A recent multicenter, ran-
domized, placebocontrolled study with 15,411 participants and
a mean follow-up duration of 3.2 years showed the subunit
vaccine efficacy was between 96.6% and 97.9% for all age
groups (50–59, 60–69, .70). Around 11% of patients devel-
oped grade 3 systemic or localized solicited adverse events,24–26
however.
The subunit vaccine showed so much promise that the ACIP and
CDC now recommends the subunit vaccine for healthy patients 50
and older, and they no longer recommend the live zoster vaccine as
first-line therapy.8,15,27 The subunit vaccine might prove to be
more effective in aging adults. In fact, a recent study confirmed
that in adults age 60 or older, 9 years after receiving the subunit
FIG. 3. Resolving pseudodendrite. vaccine, humoral, and cellular immunity remained above

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A. R. Davis and J. Sheppard Eye & Contact Lens  Volume 45, Number 5, September 2019

TABLE 2. ACIP Recommendations for Herpes Zoster Vaccination

General Population Recommendation

Immunocompetent adults .50 Immunize all irrespective of previous vaccination. No screening needed.
Note: After the first dose, second dose needed 2–6 months subsequently.
Immunocompetent adults .60 May be vaccinated with the ZVL.
Special populations
History of HZ or HZO Adults should be immunized with RZV after resolution.
Those with chronic medical illnesses Should be immunized with RZV.
Immunocompromised 1). Low-dose immunosuppression: Vaccinate with RZV.
2). Anticipating immunosuppression: Vaccinate with RZV.
3). Recovering from an immunosuppressing illness: Vaccinate with RZV.
4). Immunocompromised or on high-dose immunosuppressant: No recommendation
currently as it has not been studied.
VZV negative Follow guidelines regarding varicella vaccination. RZV not indicated.
Precautions Current HZ or HZO infection. Pregnant or nursing.
Contraindications Anaphylactic reaction to any component of the RZV.

Given the greater long-term efficacy of the RZV, it is now recommended for almost all groups.
Source: self-created from Ref. 30.
HZ, herpes zoster; HZO, herpes zoster ophthalmicus; VZV, varicella-zoster virus.

prevaccination levels in all age groups. Schwarz et al.28 predicted 2. Kawai K, Gebremeskel BG, Acosta CJ. Systematic review of incidence and
immune responses would remain above baseline for 15 years. complications of herpes zoster: Towards a global perspective. BMJ Open
2014;4:e004833.
The efficacy and long-term persistence of the new vaccine begs
3. Kalogeropoulos CD, Bassukas ID, Moschos MM, et al. Eye and periocular
the question, should we also vaccinate patients with the skin involvement in herpes zoster infection. Med Hypothesis Discov Innov
recombinant vaccine if they already received ZLV? Grupping Ophthalmol 2015;4:142–156.
et al.26 studied this particular question and in 430 patients pre- 4. Gershon AA, Gershon MD, Breuer J, et al. Advances in the understanding
viously vaccinated with Zostavax, and Shingrix proved safe and of the pathogenesis and epidemiology of herpes zoster. J Clin Virol 2010;
effective. 48(Suppl 1):S2–S7.
5. Vemulakonda GA, Pepose JS, Van Gelder RN. Acute Retinal Necrosis
The ACIP recommends the subunit vaccine for healthy patients Syndrome, 6th ed. Amsterdam, Netherlands, Elsevier Inc., 2013. doi:
50 years and older, regardless if they have received the ZLV. The 10.1016/B978-1-4557-0737-9.00088-6.
RZV is now the preferred vaccine and the use of ZLV should be 6. Morrison VA, Johnson GR, Schmader KE, et al. Long-term persistence of
reserved for patients 60 or older who are allergic to Shingrix. It has zoster vaccine efficacy. Clin Infect Dis 2015;60:900–909.
been theorized that the new recombinant vaccine will also prove 7. Vrcek I, Choudhury E, Durairaj V. Herpes zoster ophthalmicus: A review
for the internist. Am J Med 2017;130:21–26.
safe for immunocompromised individuals. As of now, data 8. Opstelten W, van Essen GA, Moons KG, et al. Do herpes zoster patients
regarding the safety profile of the RZV in immunocompromised receive antivirals? A Dutch national survey in general practice. Fam Pract
individuals have not been analyzed for the ACIP to provide 2005;22:523–528.
a recommendation. Safety data will need to be analyzed to 9. Chan AY, Conrady CD, Ding K, et al. Factors associated with age of onset
determine whether the new recombinant vaccine is safe for of herpes zoster ophthalmicus. Cornea 2015;34:535–540.
10. Tran KD, Falcone MM, Choi DS, et al. Epidemiology of herpes zoster
immunocompromised patients. Of note, there has been a report ophthalmicus: Recurrence and chronicity. Ophthalmology 2016;123:
of HZ stromal keratitis reactivation after use of the RZV.29 As of 1469–1475.
now, long-term data are needed to better understand uncommon 11. Anderson E, Fantus RJ, Haddadin RI. Diagnosis and management of herpes
complications of the new immunologic adjuvant used in the RZV zoster ophthalmicus. Dis Mon 2017;63:38–44.
and to draw further conclusions regarding its safety. Table 2, ACIP 12. Bowling B. Cornea. In: Clinical Ophthalmology. Amsterdam, Netherlands,
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Netherlands, Elsevier Inc., 2017. doi:10.1016/B978-0-323-35757-9.00078-9.
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CONCLUSION zoster virus in a patient with AIDS. Br J Med Med Res 2015;5:1381–1386.
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Herpes zoster ophthalmicus is a serious and slight threatening Amsterdam, Netherlands, Elsevier Ltd, 2018. doi:10.1016/B978-1-4557-
illness. Widespread vaccination efforts are pivotal in preventing 3984-4.00114-7.
varicella and subsequent HZ. Primary care providers and ophthal- 16. Vázquez M. Varicella zoster virus infections in children after the introduc-
mologist should serve on the front line in the effort to eradicate tion of live attenuated varicella vaccine. Curr Opin Pediatr 2004;16:80–84.
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